Glioblastomas (GBMs) are the most aggressive tumor type of the central nervous system, mainly due to their high invasiveness and innate resistance to radiotherapy and chemotherapy, with temozolomide (TMZ) being the current standard therapy. Recently, brachyury was described as a novel tumor suppressor gene in gliomas, and its loss was associated with increased gliomagenesis. Here, we aimed to explore the role of brachyury as a suppressor of glioma invasion, stem cell features, and resistance to TMZ. Using gene-edited glioma cells to overexpress brachyury, we found that brachyury-positive cells exhibit reduced invasive and migratory capabilities and stem cell features. Importantly, these brachyury-expressing cells have increased expression of differentiation markers, which corroborates the results from human glioma samples and in vivo tumors. Glioma cells treated with retinoic acid increased the differentiation status with concomitant increased expression of brachyury. We then selected TMZ-resistant (SNB-19) and TMZ-responsive (A172 and U373) cell lines to evaluate the role of brachyury in the response to TMZ treatment. We observed that both exogenous and endogenous brachyury activation, through overexpression and retinoic acid treatment, are associated with TMZ sensitization in glioma-resistant cell lines. In this study, we demonstrate that brachyury expression can impair aggressive glioma features associated with treatment resistance. Finally, we provide the first evidence that brachyury can be a potential therapeutic target in GBM patients who do not respond to conventional chemotherapeutic drugs.

胶质母细胞瘤 (GBM) 是中枢神经系统中最具侵袭性的肿瘤类型，主要是由于其高侵袭性和对放疗和化疗的先天抵抗力，替莫唑胺 (TMZ) 是当前的标准疗法。最近，brachyury 被描述为胶质瘤中的一种新的肿瘤抑制基因，它的缺失与胶质瘤发生的增加有关。在这里，我们旨在探索 brachyury 作为胶质瘤侵袭、干细胞特征和对 TMZ 抗性的抑制因子的作用。使用基因编辑的神经胶质瘤细胞过度表达brachyury，我们发现brachyury 阳性细胞表现出降低的侵袭和迁移能力以及干细胞特征。重要的是，这些表达brachyury 的细胞增加了分化标志物的表达，这证实了来自人类神经胶质瘤样本和体内肿瘤。用视黄酸处理的胶质瘤细胞增加了分化状态，同时增加了 brachyury 的表达。然后我们选择了 TMZ 抗性 (SNB-19) 和 TMZ 反应性 (A172 和 U373) 细胞系来评估 brachyury 在对 TMZ 治疗的反应中的作用。我们观察到外源性和内源性 brachyury 激活，通过过表达和视黄酸处理，与胶质瘤抗性细胞系中的 TMZ 致敏有关。在这项研究中，我们证明了 brachyury 表达可以损害与治疗抵抗相关的侵袭性胶质瘤特征。最后，我们提供了第一个证据，表明 brachyury 可以成为对常规化疗药物无反应的 GBM 患者的潜在治疗靶点。